Aberrant production of IL-17 cytokines, primarily by T helper-17 (Th17) cells, has been implicated in the development of many inflammatory and autoimmune diseases, such as Psoriasis, Multiple Sclerosis (MS) and Rheumatoid Arthritis (RA). These and other similarly debilitating diseases associated with these cytokines afflict many millions of Americans and, in addition, cause highly significant economic burdens. IL-17 (IL-17A) and the functionally and structurally closely related IL-17F are the signature cytokines of Th17 cells; they are members of the larger IL-17 cytokine family, which also includes IL-17C and IL-17E (IL-25), among others. IL-25 has been associated with Th2-type responses and, when dysregulated, may contribute to the development of Asthma. IL-17A and F are not only produced by Th17 cells, but also by a several innate T cells and by innate lymphocytes type 3 (ILC3s), while IL-25 appears to be produced primarily by epithelial cells. IL-17A and F are particularly important in defense of extracellular bacteria and fungi. All IL-17 family cytokines signal via an adaptor protein named CIKS, previously cloned in our laboratory. In the past we have reported on the functional importance of CIKS in collagen-induced arthritis (CIA), a mouse model of RA, and in SLE, which develops spontaneously in mice lacking the inhibitory FcgammaR2b protein; CIKS was particular important in development of lupus nephritis, the potentially most fatal form of the disease The latter finding was the first report to clearly implicate a role for IL-17 cytokines in local inflammation in kidneys, i.e. the development of glomerulonephritis. In FY 2014 we have now demonstrated that CIKS could also be a potential target for therapeutic intervention in psoriasis, a disease that has been closely linked to the actions of the IL-17 cytokine. Mice lacking CIKS were largely protected from the development of imiquimod-induced psoriatic inflammation, a mouse model that closely mimics many aspects of the human disease. Dissecting this disease model further in order to elucidate how the aberrantly produced IL-17 contributes to pathogenesis, we discovered that IL-17 targeted different cell types to cause the diverse manifestations of the disease. Signaling by IL-17 into keratinocytes themselves contributed to the hyper-proliferation of these cells, and it was essential for blocking the keratinization process (terminal differentiation), i.e. the formation of the most outer layer of the skin that functions as a physically barrier. In addition, signaling into keratinocytes was critical for neutrophil accumulation in the epidermis and thus formation of abscesses. We furthermore demonstrated that IL-17 signaling into dermal cells, in particular dermal fibroblasts, promoted the production of more IL-17 by innate T cells and also further enhanced cellular infiltration into the dermis. These insights revealed how IL-17 contributed to psoriatic inflammation in multiple ways, providing an explanation as to why this cytokine appears to be so central to the development of this disease.